Long non-coding RNA FENDRR is implicated in progression of several cancers, but its exact role and mechanism in hepatocellular carcinoma (HCC) are largely unknown. In this study, we investigated the expression and biological roles of FENDRR in HCC tissues and cell lines. We found that the expression levels of FENDRR were significantly down-regulated in HCC tissues and cells. FENDRR overexpression could inhibit the growth of HCC cells in vitro and in vivo. Moreover, up-regulation of FENDRR suppressed the migration and invasion of HCC cells. Mechanistically, we demonstrated that FENDRR interacted directly with Glypican-3 (GPC3) promoter and methylated GPO promoter, which led to down-regulation of GPC3 expression. Ectopic expression of GPC3 ablated the inhibitory effects of FENDRR on HCC cell proliferation, migration and invasion. Taken together, we provided the first evidence for the inhibitory activity of FENDRR in HCC, which is causally linked to targeting GPC3 at the epigenetic level. Restoration of FENDRR may be a potential approach to prevent HCC progression and metastasis. (C) 2018 Elsevier Inc. All rights reserved.